Immune Modulation During Palynziq® Treatment in Adults (IMPALA)

NCT07477691 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: 165-4012021-005058-27
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 12

Brief Summary

Study 165-401 is a Phase 4, open-label study designed to examine the concomitant use of methotrexate (MTX) to suppress immune responses to Palynziq and improve tolerability and efficacy in adults with PKU.

Conditions

Phenylketonuria

Keywords

PKU; Phenylketonuria; Pegvaliase; Palynziq; Methotrexate; Immune Response; Safety; Immune Modulation; BMN 165-401; Hyperphenylalaninemia; Enzyme Substitution Therapy; Pharmacologic Immunosuppression

Outcome Measures

Primary Outcomes (2)

• Change in blood Phe levels from baseline to Week 25 and Week 49

  To evaluate blood Phe response in adults with PKU co-administered Palynziq with MTX for 6 months

  Baseline to Week 25 and Baseline to Week 49

• Anti-PEG IgG, IgM, anti-PAL IgG, IgM levels at Weeks 5, 9, 25, and 49

  To evaluate the ability of MTX to modulate the immune response to Palynziq in adults with PKU

  Baseline to Week 5, Week 9, Week 25, and Week 49

Secondary Outcomes (2)

• Incidence of TEAEs

  Baseline through Week 49

• Trough Palynziq plasma PK

  Baseline through Week 49

Other Outcomes (2)

• Change in IgG-C3d CIC, C3, C4 levels from baseline to Weeks 9, 25, and 49

  Baseline to Weeks 9, 25, and 49

• Percentage of participants in Cohort B that have escalated from dose at enrollment

  Baseline to Week 24 and Week 48

Study Arms (2)

Palynziq naïve

EXPERIMENTAL

Individuals with uncontrolled blood phenylalanine (Phe) \> 600 μmol/L on existing management who have never been treated with Palynziq. Participants will have a 4-week Screening Period, followed by a 4-week MTX Tolerability Period during which only MTX will be administered. If MTX is tolerated during the MTX Tolerability Period, the participant will then enter the 24-week Combination Treatment Period during which MTX + Palynziq will be administered concurrently. After completion of Week 24 (Combination Treatment Period), MTX will be discontinued for both cohorts and Palynziq only will continue for another 24 weeks (to Week 49).

Biological: Pegvaliase; Drug: Methotrexate

Palynziq experienced

EXPERIMENTAL

Individuals who have uncontrolled blood Phe \> 600 μmol/L after ≥ 24 consecutive weeks of treatment with Palynziq, are on a current dose of ≥ 20mg/day and are unable to further dose escalate (Palynziq experienced). Participants will have a 4-week Screening Period. Participants will then have 24 weeks of concurrent MTX + Palynziq treatment (Combination Treatment Period): participants will be assessed for MTX tolerability during the first 4 weeks of MTX + Palynziq (MTX Tolerability Period) and then receive another 20 weeks of MTX + Palynziq. After completion of Week 24 (Combination Treatment Period), MTX will be discontinued for both cohorts and Palynziq only will continue for another 24 weeks (to Week 49).

Biological: Pegvaliase; Drug: Methotrexate

Interventions

Pegvaliase BIOLOGICAL

Pegvaliase (Palynziq) administered by subcutaneous injection. Dosing follows U.S. Prescribing Information and investigator judgement.

Also known as: Palynziq

Palynziq experienced; Palynziq naïve

Methotrexate DRUG

Oral methotrexate 15 mg administered once weekly during the Tolerability Period and the Combination Treatment Period.

Also known as: MTX

Palynziq experienced; Palynziq naïve

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults between 18 and 65 years old
• Have a confirmed diagnosis of phenylketonuria (PKU)
• Are in generally good health based on medical evaluation
• Are willing and medically eligible to receive Palynziq and methotrexate (MTX) Cohort A: Have never taken Palynziq before and are willing to start it during the study Cohort B: Have blood \> 600 μmol/L after taking Palynziq for at least 24 weeks, are on a daily dose of at least 20mg and unable to increase the dose further
• Agree to use required contraception if they or their partner could become pregnant
• Are willing to carry two epinephrine devices at all times during Palynziq treatment

You may not qualify if:

• Pregnant, breastfeeding, planning to become pregnant, planning to father a child, or not using effective birth control if applicable
• Have a known severe allergy or hypersensitivity reaction to methotrexate (MTX), Palynziq, or other PEG-containing medications
• Have a serious active infection or a history of severe or recurrent infections
• Have significant medical conditions that may affect safety or participation (such as serious heart, lung, liver, kidney, immune, neurological, psychiatric, or cancer-related conditions)
• Have a history of substance or alcohol abuse within the past 12 months
• Have had an organ transplant or are taking chronic immunosuppressive medications
• Are currently taking medications that are not allowed in the study, including other PKU treatments besides Palynziq
• Are using, or plan to use, injectable PEG-containing medications other than Palynziq during the study
• Have major surgery planned during the study participation period
• Are currently participating in another clinical study involving Palynziq
• In the opinion of the study doctor, are not a suitable candidate for the study or may have difficulty complying with study requirements

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (12)

UCLA Dept. of Human Genetics

Los Angeles, California, 90095, United States

NOT YET RECRUITING

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

NOT YET RECRUITING

University Of South Florida Medical Center

Tampa, Florida, 33613, United States

NOT YET RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

NOT YET RECRUITING

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

NOT YET RECRUITING

University of Minnesota Medical School

Minneapolis, Minnesota, 55455, United States

NOT YET RECRUITING

University of Rochester Medical Center (URMC)

Rochester, New York, 14642, United States

NOT YET RECRUITING

Oregon Health & Science University (OHSU) - PARENT

Portland, Oregon, 97239, United States

NOT YET RECRUITING

University of Pittsburgh Medical Center (UPMC) - Children's Hospital of Pittsburgh

Philadelphia, Pennsylvania, 19104, United States

NOT YET RECRUITING

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

RECRUITING

University of Utah Hospital

Salt Lake City, Utah, 84108, United States

NOT YET RECRUITING

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Phenylketonurias

Interventions

pegvaliase; Methotrexate

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Medical Director, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Central Study Contacts

Trial Specialist

CONTACT

1-800-983-4587; medinfo@bmrn.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 13, 2026
• First Posted: March 17, 2026
• Study Start: May 29, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: June 17, 2026

Record last verified: 2026-06

Locations

US (12)